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Emergence of Antimicrobial Resistance

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Title: Emergence of Antimicrobial Resistance


1
Emergence of Antimicrobial Resistance
  • Ebbing Lautenbach, MD, MPH
  • Assistant Professor of Medicine and Epidemiology
  • Associate Hospital Epidemiologist, Hospital of
    the University of Pennsylvania
  • Center for Clinical Epidemiology Biostatistics
  • University of Pennsylvania School of Medicine

2
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • Clinical Impact on resistance
  • Strategies to curb further emergence of
    resistance

3
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • Clinical Impact on resistance
  • Strategies to curb further emergence of
    resistance

4
(No Transcript)
5
Emergence of Gram - Resistance
FQ-R P. aeruginosa
Ceftaz-R K. pneumoniae
FQ-R E. coli
6
New Agents with Expanded in Vitro
Gram-Positive Activity


7
New Agents with Expanded Gram Negative Activity
8
Trends in Development of New Antibacterials
R2 0.99
Total New Antibacterial Agents
p 0.007 by linear regression New antibacterial
agent ? new molecular entity (NME) with
antimicrobial properties, administered for
systemic infection topical agents,
immunomodulators excluded
Edwards J, ICAAC, 2003
9
Potential Reasons for Pharmaceutical Company
Shifts Away From Anti-infective Development
  • Shift in demographics of population to elderly
  • Need for treatment of chronic diseases
  • Antibiotics become auto-obsolete
  • Thought leaders advocating conservative use
  • Increasing standards for efficacy and safety
    evaluation
  • Increasingly complex patients in clinical trials
  • Significantly increased costs in clinical trials
  • Attractive to develop agents used for life of
    patients

Edwards J, ICAAC, 2003
10
Pharmaceutical RD 15 largest by revenue
11
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • Clinical Impact on resistance
  • Strategies to curb further emergence of
    resistance

12
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • 2 examples
  • Fluoroquinolone resistance
  • Vancomycin-resistant enterococci
  • Clinical Impact on resistance
  • Strategies to curb further emergence of
    resistance

13
Importance of FQ Resistance
  • One of the most commonly used antibiotic
    classes1,2
  • Most common antibiotic used in nursing homes3
  • Broad spectrum
  • Oral bioavailability
  • Long half-life
  • Well tolerated

1. Thomson, J Antimicrob Chemother, 1994 2. Lee,
Am J Infect Control, 1998 3. Steinman, Ann Intern
Med, 2003
14
Quinolones
  • DNA Gyrase
  • Supercoiling
  • 4 subunits
  • 2 A subunits (gyrA gene)
  • 2 B subunits (gyrB gene)
  • Topoisomerase IV
  • Acts in terminal stages of DNA replication
  • Separates newly replicated daughter strands
  • 2 subunits
  • ParC (GrlA in S. aureus)
  • ParE (GrlB in S. aureus)

DNA gyrase (B subunit)
15
Trends in FQ Resistance
  • Surveillance study
  • GN bacilli
  • ICUs from 43 states
  • 1994 2000
  • 35,790 isolates
  • Cipro susceptibility decreased from 86 to 76

No difference across teaching vs
non-teaching 500 beds vs
Neuhauser MM, JAMA 2003289885
16
FQ Resistance vs FQ Use
PA (r0.976 pNeuhauser MM, JAMA 2003289885
17
FQR-EC and FQ Use
Lautenbach, SHEA, 2002
18
FQR-EC and the Dow Jones IA
19
Risk Factors for Nosocomial FQ Resistance in E.
coli and K. pneumoniae
  • Case-control study (1/1/98 6/30/99)
  • Sites
  • Hospital of the Univ. of Penn (HUP)
  • Presbyterian Medical Center (PMC)
  • Subjects identified through Clinical Micro Lab at
    HUP
  • Study subjects
  • 123 cases (FQ-resistant)
  • 70 controls (FQ-susceptible)
  • Review of inpatient medical records

Lautenbach, Arch Intern Med 20021622469
20
Multivariable Model
Lautenbach, Arch Intern Med 20021622469
21
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • 2 examples
  • Fluoroquinolone resistance
  • Vancomycin-resistant enterococci
  • Clinical Impact on resistance
  • Strategies to curb further emergence of
    resistance

22
Importance of Enterococci
  • 3rd most common hospital pathogen
  • 10-12 of all nosocomial infections
  • 3rd most common cause of BSI
  • 3-4 per 10,000 discharges
  • 1980s incidence of enterococcal bacteremia in
    teaching hospitals increased up to 197 1
  • 1. NNIS, Am J Med 199191(suppl 3B)86S

23
Emergence of VRE
  • First isolated in vitro in 1969 1
  • Described clinically in 1988 2,3
  • Mechanism of resistance
  • Alteration of cell wall precursors
  • Several resistance phenotypes
  • VanA and VanB most clinically significant
  • 1. Toala, Am J Med Sci 1969258416 2.
    Leclercq, NEJM 1988319157 3. Uttley,
    Lancet 1988157

24
Progression of Vancomycin Resistance Enterococci
Martone WJ. Infect Control Hosp Epidemiol.
199819539-545. NNIS Antimicrobial Resistance
Surveillance Report. 1999. (www.cdCgov/ncidod/hip/
NNIS/AR_Surv1198.htm).
through June 1999
25
Risk Factors An Exhaustive (ing) List
  • Age
  • Duration of hospitalization
  • ICU admission
  • Renal insufficiency
  • Immunosuppression
  • Neutropenia
  • Hematologic malignancy
  • Solid organ transplant
  • Bone marrow transplant
  • AIDS
  • Prior Surgery
  • Antibiotics - General
  • Number / Duration
  • Antibiotics - Specific
  • Almost all implicated
  • Diarrhea / C. difficile
  • Central venous catheter
  • Urinary catheter
  • Prior Colonization
  • Exposure to VRE source
  • VRE-infected patient
  • Inanimate Object
  • Health Care Worker

26
Risk factors for VRE (HUP)
  • Case control study (1/1/93 - 12/31/95) HUP
  • 260 cases enterococcal bacteremia
  • 72 VRE
  • Risk factor OR (95CI) p value
  • Vancomycin use 3.0 (1.4,6.4) .005
  • Renal insufficiency 4.4 (2.0,9.7)
  • Neutropenia 6.3 (1.5,26.7) .013

Lautenbach, Infect Control Hosp Epidemiol,
199920318
27
VRE Risk Factors
28
Risk Factors Modifiable Variables
  • Age
  • Duration of hospitalization
  • ICU admission
  • Renal insufficiency
  • Immunosuppression
  • Neutropenia
  • Hematologic malignancy
  • Solid organ transplant
  • Bone marrow transplant
  • AIDS
  • Prior Surgery
  • Antibiotics - General
  • Number / Duration
  • Antibiotics - Specific
  • Almost all implicated
  • Diarrhea / C. difficile
  • Central venous catheter
  • Urinary catheter
  • Prior Colonization
  • Exposure to VRE source
  • VRE-infected patient
  • Inanimate Object
  • Health Care Worker

29
Exposure to VRE Source
  • To develop VRE infection, one must first be
    exposed to the organism
  • Extent of exposure is related to other risk
    factors
  • Duration of hospitalization
  • ICU admission
  • Age
  • Greater severity of illness
  • Indwelling devices

30
Sources of VRE Acquisition
  • VRE-infected patients
  • Colonization pressure 1
  • Inanimate objects
  • Gowns, Bed linens, Cabinets, ECG wires, Floors,
    etc.
  • Room contamination
  • 50 of rooms may become contaminated
  • May remain viable up to several months
  • Healthcare workers?
  • 1. Bonten, Arch Intern Med 19981581127

31
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • Clinical impact on resistance
  • Strategies to curb further emergence of
    resistance

32
Impact of Antimicrobial Resistance
  • Increased morbidity / mortality 1,2
  • Increased cost
  • Estimated annual excess hospital costs in the
    United States 100 million - 30 billion3

1. Patton, Med Clin North Am, 1991 2. Cohen,
Science, 1992 3. Phelps, Med Care, 1989
33
Impact of Resistance on Antibiotic Use
  • Increased complexity of empiric antibiotic
    coverage
  • Greater empiric use of antibiotics
  • Increased use of broad spectrum antibiotics
  • Perpetuates the cycle of resistance

34
Impact of FQ Resistance on Clinical Outcome
  • Retrospective cohort design
  • All patients with clinical E. coli or K.
    pneumoniae isolates
  • 123 patients with FQ-resistant isolate
  • 70 patients with FQ-susceptible isolate
  • January 1, 1998 - June 30, 1999
  • Sites
  • Hospital of the Univ. of Penn (HUP)
  • 725-bed academic medical center
  • Presbyterian Medical Center (PMC)
  • 344-bed urban community hospital

Lautenbach et al, SHEA, 2002
35
Results Mortality
P0.05
Lautenbach, SHEA, 2002
36
Multivariable Model Risk Factors for Mortality
Lautenbach, SHEA, 2002
37
Time to Effective Therapy
Lautenbach et al, SHEA, 2002
38
Impact of VRE on Emergence of Other Resistance
Patterns
  • Resistance transferable to S. aureus in vitro 1
  • 8-month prospective study of S. aureus and VRE
    co-colonization in the GI tract 2
  • Of 37 patients colonized with VRE, 23 (62) had
    S. aureus recovered from stool
  • Of these, 20 (87) had MRSA
  • 25 of stools with S. aureus contained 1,000,000
    organisms/gram of stool

1. Noble WC, FEMS Microbiol Lett 1992 72195 2.
Ray AJ, Clin Infect Dis 2003 37875
39
Glycopeptide Resistance in S. aureus
40
VISA Isolates PFGE Analysis
Lane 1-S. Aureus Lane 2-MRSA Lane 3-VISA
(pt1) Lane 4-MRSA (pt1) Lane 5-VISA (pt2)
Smith, NEJM 1999340493
41
VRSA - 2002
VanA
Chang S, N Engl J Med 20033481342
42
Outline
  • Recent trends in emerging antibiotic resistance
  • Epidemiology of resistance
  • Clinical impact on resistance
  • Strategies to curb further emergence of
    resistance

43
Prevention of Spread VRE
  • How do findings relate to infection risk?
  • Only a minority of patients become colonized when
    cared for in a contaminated room 1
  • Elucidation of mechanisms of VRE acquisition
  • Implement more effective infection control
    interventions
  • Enhanced surveillance
  • Patients infected or colonized with VRE have
    equal potential for transmission
  • Patient transfer between facilities
  • 1. Bonten, Lancet 19963481615

44
Antibiotic Use Is There Room for Improvement?
45
  • The desire to ingest medicines is one of the
    principal features which distinguish man from the
    animals
  • Osler W. Aecquanimitas,1920

46
Implications Addressing FQ Overuse / Misuse
  • On whom/Where are they being used?
  • Inpatient
  • Outpatient
  • Emergency Departments
  • Why/How are they being used?
  • Indications
  • Dose/duration

47
How are FQs Used Appropriateness in Inpatients
Ena, Diagn Microbiol Infect Dis 1998
48
Appropriateness of FQ Use EDs
  • FQ Drug Use Evaluation (DUE)
  • Sites 2 Academic Medical Center Emergency
    Departments (EDs)
  • Subjects 100 patients seen in EDs, then
    discharged
  • Appropriateness (of indication) of therapy judged
    by existing institutional guidelines
  • www.med.upenn.edu/bugdrug
  • 3 independent ID reviewers

Lautenbach, Arch Intern Med 2003163601
49
Appropriateness of ED FQ Use
81 of courses inappropriate
Lautenbach, Arch Intern Med 2003163601
50
Appropriateness by Site of Infection
p0.76
Lautenbach, Arch Intern Med 2003163601
51
Appropriateness of FQ Use EDs
  • 19/100 (19) patients received appropriate FQ
    therapy (judged by indication)
  • 14 received both an incorrect dose duration
  • 4 received either an incorrect dose or duration
  • 1 received the correct dose and duration
  • Variation of FQ use by ED
  • ED1 (training program) 74 inappropriate
  • ED2 (no training program) 86 inappropriate
  • OR (95CI) 0.39 (0.14, 1.09)

Lautenbach, Arch Intern Med 2003163601
52
Potential Strategies
  • Guidelines
  • Antibiotic cycling
  • Antimicrobial optimization

53
Potential Strategies
  • Guidelines
  • Antibiotic cycling
  • Antimicrobial optimization

54
Awareness and Use of CAP Guidelines
  • Survey study of 621 physicians
  • ATS CAP guidelines / local CAP guidelines
  • 7 Pittsburgh area hospitals
  • 1 University
  • 3 community teaching
  • 3 community non-teaching
  • 345/621 (56) responded
  • Generalists (79)
  • ID (6)
  • Pulmonologist (5)

Switzer GE, J Gen Intern Med 200318816
55
Awareness and Use of CAP Guidelines
n345
Switzer GE, J Gen Intern Med 200318816
56
Predictors of Use of ATS Guidelines
Goldberg Personality Scale
Switzer GE, J Gen Intern Med 200318816
57
Awareness and Use of CAP Guidelines
  • 6 of 7 study hospitals had local guidelines for
    CAP
  • 290 respondents from the 6 hospitals
  • 41 reported that no local guidelines existed
  • 30 of respondents reported they used the
    guideline more than half of the time in CAP
    therapy
  • 48 respondents from the hospital without a
    guideline,
  • 14 said it their hospital did have a guideline
  • Local CAP guideline use was associated with
  • Practicing as a generalist OR0.10 95CI
    (0.01-0.89)
  • Positive attitude toward guidelines OR1.05
    95CI (0.99-1.11)

Switzer GE, J Gen Intern Med 200318816
58
Limitations of Guidelines
  • Discrepancies across guidelines
  • Lack of RCT data to support recommendations
  • Little regional/local susceptibility data
  • Poor correlation between in vitro resistance and
    clinical response
  • Failure to consider future emergence of resistance

Luh JY, Arch Intern Med 20031631617
59
Potential Strategies
  • Guidelines
  • Antibiotic cycling
  • Antimicrobial optimization

60
Antibiotic Cycling
  • Periodic removal of certain agents / classes
  • Goals
  • Prevention of VAP
  • Curb emergence of antibiotic resistance
  • Optimize empiric antibiotic selection
  • Assumptions
  • Resistance emerges through selective pressure
  • Strict antibiotic control
  • Closed population
  • No patient to patient transmission
  • No co-selection of resistance

61
Antibiotic Cycling
  • Prospective cohort study conducted in ICU
  • University of Virginia
  • General, trauma, or transplant surgery patients
  • 2 year study
  • 1 year non-protocol driven antibiotic use
  • 1 year of rotating empirical antibiotic
    assignment
  • November 1997 October 1999

Raymond DP, Crit Care Med 2001291101
62
Antibiotic Cycling
a - add clindamycin for pneumonia if aspiration
suspected b imipenem or meropenem
c- add
ampicillin or vancomycin if Enterococcus is
suspected
Raymond DP, Crit Care Med 2001291101
63
Antibiotic Cycling
  • Variable Year 1 Year 2 p value
  • Resistant GPC Infections 14.6 7.8
  • Resistant GNB Infections 7.7 2.5
  • Infection-related mortality 9.6 2.9
  • Liver disease 19 (10.8) 8 (5.6)
  • Transplantation 27 (15.3) 6 (4.2) 0.001
  • All variables per 100 admissions
  • Limitations
  • Concurrent ceftazidime to cefepime formulary
    switch
  • Concurrent infection control interventions

Raymond DP, Crit Care Med 2001291101
64
Potential Strategies
  • Guidelines
  • Antibiotic cycling
  • Antimicrobial optimization

65
Antimicrobial Optimization
  • Decrease unnecessary antibiotic use
  • Develop / apply guidelines for antibiotic use
  • Tailor empiric antibiotic selection to particular
    situation
  • Patient specific
  • Maintain broad choice of agents
  • Several approaches
  • Human
  • Computer

66
Antimicrobial Optimization
  • Decrease unnecessary antibiotic use
  • Develop / apply guidelines for antibiotic use
  • Tailor empiric antibiotic selection to particular
    situation
  • Patient specific
  • Maintain broad choice of agents
  • Several approaches
  • Human
  • Computer

67
Antibiotic Management Programs
  • University of Pennsylvania
  • 1993 - Antibiotic management program (AMP)
  • Formulary redesigned
  • Guidelines developed
  • AMT team
  • Approval of restricted agents
  • Streamlining of therapy

Gross R, Clin Infect Dis 200133289
68
Antibiotic Management Programs
Gross R, Clin Infect Dis 200133289
69
Antimicrobial Optimization
  • Decrease unnecessary antibiotic use
  • Develop / apply guidelines for antibiotic use
  • Tailor empiric antibiotic selection to particular
    situation
  • Patient specific
  • Maintain broad choice of agents
  • Several approaches
  • Human
  • Computer

70
Computer Support
71
Computer Decision Support
  • Prospective before-after study of a computerized
    anti-infectives management program
  • 12-bed ICU
  • LDS Hospital, Salt Lake City
  • June 1992 June 1995
  • 2 year before period
  • 1 year after period

Evans RS, NEJM 1998338232
72
Computer Decision Support
  • Computer system
  • Data incorporated
  • Patient information admission diagnosis, WBC
    count, temperature, surgical data, chest
    radiograph, microbiology data, pathology data,
    serologic data, allergies, past infection
  • Institution information 5-year antibiogram
  • Output
  • Suggest antibiotic regimen that would cover the
    identified and potential pathogens

Evans RS, NEJM 1998338232
73
Computer Decision Support
  • Variable Before (n766) After (n203) p value
  • different abx ordered 2.0 (1.9, 2.1) 1.5 (1.3,
    1.7)
  • Duration of abx (hrs) 214 (177-251) 103
    (45-160)
  • abx doses 23.6 (20.326.9) 11.4
    (6.2-16.7)
  • ICU Length of stay (ds) 4.9 (4.1-5.8) 2.7
    (1.5-4.0)
  • Total Length of stay 12.9 (11.5-14.4) 10.0
    (7.7-12.3)
  • Total hospital cost 35K (31K-39K) 26K
    (20K-32K)
  • Includes only those patients for whom computer
    regimen was followed
  • Values are means per patient and 95CIs

Evans RS, NEJM 1998338232
74
Trends in Antimicrobial Prescribing
  • Cross sectional survey
  • National Ambulatory Medical Care Survey (NCAMS)
  • Overall abx use
  • Adults 13 10 (p
  • Peds 33 22 (p
  • Broad Spectrum abx use
  • Adults 24 48 (p
  • Peds 23 40 (p

Steinman MA, Ann Intern Med 2003138525
75
Trends in Antimicrobial Prescribing
Steinman MA, Ann Intern Med 2003138525
76
Conclusions
  • Antimicrobial resistance increasing
  • Negative impact of resistance on clinical
    outcomes
  • Many potential interventions
  • All require more study
  • Judicious use of current agents critical to
    preserve future use

77
Emergence of Antimicrobial Resistance
  • Ebbing Lautenbach, MD, MPH
  • Assistant Professor of Medicine and Epidemiology
  • Associate Hospital Epidemiologist, Hospital of
    the University of Pennsylvania
  • Center for Clinical Epidemiology Biostatistics
  • University of Pennsylvania School of Medicine
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